ETHACRYNIC ACID

Chemistry - A loop diuretic, ethacrynic acid occurs as a white or nearly white, odorless or practically odorless crystalline powder. It is very slightly soluble in water and freely soluble in alcohol.

Storage, Stability, Compatibility

Ethacrynic acid tablets should be stored at room temperature in well-closed containers. An expiration date of 5 years is assigned at the time of manufacture.

Pharmacology - ETHACRYNIC ACID

Ethacrynic acid reduces the absorption of electrolytes in the ascending section ofthe loop of Henle, decreases the reabsorption of both sodium (to a much greater extent than thethiazides) and chloride, increases the excretion of potassium in the distal renal tubule, and directlyeffects electrolyte transport in the proximal tubule. The exact mechanisms of ethacrynic acid'seffects have not been established. It has no effect on carbonic anhydrase nor does it antagonizealdosterone. Ethacrynic acid increases renal excretion of water, sodium, potassium, chloride, calcium, magnesium, hydrogen, ammonium and bicarbonate.

Uses, Indications

Ethacrynic acid is a loop diuretic that shares the same indications asfurosemide (congestive cardiomyopathy, pulmonary edema, hypercalcuric nephropathy, uremia, asadjunctive therapy in hyperkalemia and, occasionally, as an antihypertensive agent). Its use has beenlargely supplanted in the armamentarium by furosemide for these indications.
Ethacrynic acid may be useful in the treatment of nephrogenic diabetes insipidus as it may cause aparadoxical decrease in urine volume. Other uses include the adjunctive treatment of hypercalcemiaand to increase the excretion of bromide in the treatment of bromide toxicity.

Pharmacokinetics - ETHACRYNIC ACID

Ethacrynic acid is absorbed rapidly and nearly completely from the GI tract.
It does not enter the CNS and accumulates in the liver. It is unknown if etha-crynic acid crosses theplacenta or enters milk. Ethacrynic acid is metabolized in the liver and also secreted via the proximaltubules into the urine. Serum half lives in humans average around one hour. Duration of effect isabout 6-8 hours after oral dosing and about 2 hours after IV administration.

Contraindications, Precautions, Reproductive Safety

Ethacrynic acid is contraindicated inpatients with anuria, who are hypersensitive to the drug or have seriously depleted electrolytes.
Ethacrynic acid is also contraindicated in human infants (safety not established).
Ethacrynic acid should be used with caution in patients with preexisting electrolyte or waterbalance abnormalities, impaired hepatic function (may precipitate hepatic coma) and diabetesmellitus. Patients with conditions that may lead to electrolyte or water balance abnormalities (e.g., vomiting, diarrhea, etc.) should be monitored carefully.
A study where pregnant dogs received 5 mg/kg daily demonstrated no teratogenic effects or effects on the pregnancy. It is unknown whether the drug enters milk.

Adverse Effects, Warnings

Ethacrynic acid may induce fluid and electrolyte abnormalities.
Patients should be monitored for hydration status and electrolyte imbalances (especially potassium, calcium and sodium). Other potential adverse effects include ototoxicity (especially in cats withhigh dose IV therapy), gastrointestinal disturbances, hematologic effects (anemia, leukopenia), weakness and restlessness. Ethacrynic acid is thought to have a greater incidence of ototoxicity and GI effects than furosemide.

Overdosage, Acute Toxicity

The LD50 in dogs after oral administration is > 1000 mg/kg andafter IV injection > 300 mg/kg. Chronic overdosing at 10 mg/kg for six months in dogs led todevelopment of calcification and scarring of the renal parenchyma.
Acute overdosage may cause electrolyte and water balance problems, CNS effects (lethargy tocoma and seizures) and cardiovascular collapse.
Treatment consists of emptying the gut after recent oral ingestion, using standard protocols. Avoidgiving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that canoccur. Aggressively monitor and treat electrolyte and water balance abnormalities supportively.
Additional y, monitor respiratory, CNS, and cardiovascular status. Treat supportively andsymptomatically if necessary.

Drug Interactions

Pharmacologic effects of theophylline may be enhanced when given with ethacrynic acid. Ototoxicity and nephrotoxicity associated with the aminoglycoside antibiotics may be increased when ethacrynic acid is also used. If used concomitantly with corticosteroids, corticotropin or amphotericin B, ethacrynic acid may increase the chance of hypokalemia development. Ethacrynic acid-induced hypokalemia may increase chances of digitalis toxicity. There may be an increased risk of GI hemorrhage when ethacrynic acid is used with corticosteroids.
Patients on aspirin therapy may need dosage adjustment as ethacrynic acid competes for renalexcretory sites. Ethacrynic acid may inhibit the muscle relaxation qualities of tubocurarine, butincrease the effects of succinylcholine. Enhanced effects may occur if ethacrynic acid is usedconcomitantly with other diuretics. The uricosuric effects of probenecid or sulfinpyrazone maybe inhibited by ethacrynic acid. Ethacrynic acid may alter the requirements of insulin or other antidiabetic agents in diabetic patients.